Researchers led by Zhentao Zhang at Wuhan University, China have discovered a cholesterol metabolite that plays a critical role in the development of Parkinson's disease in mice. Published in the open-access journal PLOS Biology on February 18th, the study shows that this metabolite is responsible for the formation of Lewy bodies and the death of dopaminergic neurons in the brain—the two major hallmarks of Parkinson's disease. Blocking its activity or preventing it from being made by the body could therefore be effective strategies for treating the disease.
Parkinson's disease develops when the protein alpha-Syn forms clumps of tiny pathological fibers in the brain called Lewy bodies, which spread from brain cell to brain cell, and eventually trigger the death of dopamine neurons. The new study focuses on what causes the spread of pathological alpha-Syn, with the authors hypothesizing that the culprit is 24-OHC, a cholesterol metabolite known to present at high levels in the brains of people with Parkinson's disease, and which increases with age.
After confirming that 24-OHC levels were higher in the blood of patients with Parkinson's disease as well as in a mouse model of the disease, the researchers blocked its production in the mouse model by knocking out the enzyme that creates it from cholesterol. This reduced both the spread of the harmful alpha-Syn fibers and the damage to the dopamine neurons in the critical part of the brain. Further experiments with neurons cultured in a dish showed that the addition of 24-OHC caused normal alpha-Syn to change into harmful alpha-Syn fibers. Injecting mice with these fibers led to greater spread of Lewy bodies, more dopaminergic neuron degeneration, and greater motor deficits than did injecting them with alpha-Syn fibers formed in the absence of 24-OHC. Drugs that prevent cholesterol from being converted to 24-OHC might therefore be an effective treatment for the disease.
The authors add, "Our findings indicate that the cholesterol 24-hydroxylase CYP46A1 plays a pivotal role in the progression of α-synuclein pathology in Parkinson's disease, highlighting its potential as a therapeutic target for Parkinson's disease."
In your coverage, please use this URL to provide access to the freely available paper in PLOS Biology: https://plos.io/4gujU08
Citation: Dai L, Wang J, Meng L, Zhang X, Xiao T, Deng M, et al. (2025) The cholesterol 24-hydroxylase CYP46A1 promotes α-synuclein pathology in Parkinson's disease. PLoS Biol 23(2): e3002974. https://doi.org/10.1371/journal.pbio.3002974
Author countries: China
Funding: see manuscript
